Revista de Farmacologia Clínica e Experimental

Abstrato

Altered Sarcoplasmic Reticulum Calcium Cycling-Targets for Heart Failure Therapy

Zemene Demelash Kifle, Mohammedbrhan Abdelwuh

Heart failure is a complex clinical syndrome with typical symptoms and signs that generally occur on exertion but can also occur at rest (particularly when recumbent), secondary to an abnormality of cardiac structure or function. There are an estimated 23 million people with HF worldwide. The contractile force in cardiomyocytes is determined by the amplitude of the Ca2+ transient generated by SR Ca2+ release via intracellular Ca2+ release channels/ryanodine receptor-2. At the cellular level, the causes of impaired cardiac myocyte relaxation include cytosolic Ca2+ overload, myofilament structural changes or dysfunction, and neurohormonal activation. Alternatively, a decrease in Ca2+ efflux or inadequate Ca2+ reuptake by the sarcoplasmic reticulum during diastole can result in intracellular Ca2+ overload in this condition. SERCA2a is validated to be the major cardiac isoform. SERCA2a is a prime target for modulation of cardiac contractility during heart failure. The dysregulation of SERCA2a is a hallmark of heart failure. Reduction in SR Ca2+ uptake results in systolic dysfunction as well as increased cytosolic Ca2+ level and susceptibility to apoptosis. Alterations in the levels of the ryanodine receptor, triadin, junctin, and calsequestrin may affect Ca2+ storage in the SR, the amount of Ca2+ which is available to be released from the SR and the amount of SR Ca2+ leak during diastole, thus contributing to the pathology of the failing heart. Histidine-rich calcium-binding protein (HRC) regulates Ca2+ homeostasis in the heart. Overexpression of FKBP12.6 reduces Ca2+ leak from the SR during diastole, thereby increasing SR-Ca2+ content, and thus increases the amount of Ca2+ available for release, which in turn increases twitch shortening amplitude. This review aims to introduce altered sarcoplasmic reticulum calcium cycling-targets for heart failure therapy.